Antibodies have emerged as a major therapeutic tool for the treatment of chronic diseases such as cancer and autoimmune disorders. One of the principal advantages of these biological agents lies in their ability to target disease-causing cells or molecules, while sparing healthy tissue and normal products of the body. However, antibodies that exhibit desired specificities often fail in pre-clinical and clinical evaluations because of inefficient targeting and/or low therapeutic activity.
A rare class of antibodies, known as SuperAntibodies, exist in nature. These are antibodies that exhibit one or more properties not usually associated with antibodies (Kohler H., et al., 1998; Kohler H., 2000). The defined class of SuperAntibodies comprises catalytic, membrane-penetrating, and autophilic antibodies and includes many antibodies exhibiting superior targeting and therapeutic properties. One example of a naturally occurring SuperAntibody is the murine TEPC-15 antibody. TEPC-15 is an autophilic antibody which targets a normally cryptic determinant of phosphorylcholine on apoptotic cells and atheroschlerotic lesions. TEPC-15 antibodies have high therapeutic efficacy due to their ability to form dimers or multimers (on cell or bacteria surfaces, after binding to antigen), which enhances apoptosis. TEPC-15 antibodies are able to form dimers and multimers due to an autophilic peptide sequence. (Kang, C-Y, et al., 1988)
It is known that a major mechanism by which therapeutic antibodies attack their target cells is through the induction of apoptosis. Apoptosis is triggered by crosslinking cellular receptors that are part of the apoptosis signal pathway. For example, crosslinking the B-cell antigen receptor by means of antibodies induces apoptosis in B-cell tumors (Ghetie M., et al., 1997). Crosslinking of cellular receptors also increases the binding avidity of an antibody to its target antigen, and thus is likely to increase all cell surface-dependent therapeutic mechanisms, such as complement-mediated killing and complement-dependent opsonization and phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), as well as enhanced inhibition of cell growth or alterations in metabolic pathways within cells through increased binding to and blockade of cellular receptors when using antibodies targeted to cellular receptors.
To enhance the therapeutic efficacy of known antibodies, others have proposed the use of hybrid molecules for therapeutic purposes wherein the hybrid molecules comprise two distinct domains covalently linked. For instance, U.S. Pat. No. 6,482,586 (issued to Arab et al.) proposes covalent hybrid compositions for use in intracellular targeting. U.S. Pat. No. 6,406,693 (issued to Thorpe et al.) proposes antibodies and conjugates for killing tumor vascular endothelial cells by binding to aminophospholipid on the luminal surface.
These are but a few of the approaches that have been used to enhance therapeutic efficacy of monoclonal antibodies that, in their native or “humanized” state, are not effective in killing their targets or triggering a biological function affording therapeutic efficacy.
There is a need for a method of enhancing the therapeutic efficacy of antibodies which have desired specificities without the use of toxic agents.